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J Zaagsma

Publications and source records attributed to J Zaagsma.

At least 55 records · Page 3Linked to original sources
PubMed1995

Beta 2- but not beta 3-adrenoceptors mediate prejunctional inhibition of non-adrenergic non-cholinergic contraction of guinea pig main bronchi.

We studied the effects of selective beta-adrenoceptor agonists on the cholinergic and non-adrenergic non-cholinergic (excitatory NANC) contractions elicited by electrical field stimulation of guinea pig main bronchi in vitro. Addition of the selective beta 2-adrenoceptor agonists, fenoterol and salbutamol, and the selective beta 3-adrenoceptor agonist, BRL 37344 (4-[2-[(2-hydroxy-2-(3-chlor-phenyl)ethyl)amino]-propyl]-phenoxyac etic acid), induced a dose-dependent inhibition of the cholinergic contraction (pD2 7.89, 6.71 and 4.56, respectively) and the excitatory NANC response (pD2 9.11, 8.16 and 7.42, respectively). Fenoterol- and BRL 37344-induced inhibition of the excitatory NANC response was blocked with high potency (pKB 8.77 and 9.07, respectively) by the selective beta 2-adrenoceptor antagonist, ICI 118,511 (erythro-1-(7-methylindan-4-yloxy)-3-(isopropylamino)-but an-2-ol). A comparable contraction induced by neurokinin A (2 or 5 nM) was also inhibited by fenoterol, salbutamol and BRL 37344, but at significantly higher concentrations than for the inhibition of the excitatory NANC response (pD2 8.72, 7.56 and 6.66, respectively). Such a preferential inhibition of electrical field stimulation- versus agonist-induced effects was not observed for cholinergic contractions (pD2 versus methacholine-induced tone 7.86, 6.93 and 5.10, respectively). The results clearly exclude the involvement of beta 3-adrenoceptors in these responses. Furthermore they show that beta 2-adrenoceptors are involved in the prejunctional inhibition of excitatory NANC contractions, presumably via modulation of tachykinin release from sensory nerves, and solely in the postjunctional inhibition of cholinergic contractions.

Adrenergic beta-Agonists↗
PubMed1995

Phosphodiesterase inhibitors reduce bronchial hyperreactivity and airway inflammation in unrestrained guinea pigs.

A new guinea pig model of allergic asthma was used to investigate the effects of low doses of the phosphodiesterase inhibitors, rolipram (phosphodiesterase IV selective), ORG 20241 (N-hydroxy-4-(3,4-dimethoxyphenyl)-thiazole-2-carboximidamide; dual phosphodiesterase III/IV inhibitor with some selectivity for the phosphodiesterase IV isoenzyme), and of theophylline (non-selective) on allergen-induced early and late phase asthmatic reactions, bronchial hyperreactivity to histamine inhalation, and airway inflammation. Theophylline (25 mg/kg i.p.) and ORG 20241 (5 mg/kg i.p.) did not affect histamine-induced bronchoconstriction, whereas rolipram (75 micrograms/kg i.p.) only slightly reduced the response to histamine at 7 h after administration. However, bronchial hyperreactivity after the early and after the late reaction was significantly reduced by theophylline, rolipram and ORG 20241, while bronchoalveolar lavage studies revealed a selective inhibition of airway inflammation by the phosphodiesterase inhibitors. Theophylline significantly reduced the number of eosinophils, neutrophils and macrophages; rolipram reduced the number of neutrophils and lymphocytes, and ORG 20241, the number of eosinophils and macrophages. None of the compounds at the dosage indicated reduced the early and late reaction when administered i.p. 1 h before allergen exposure to defined dual responding animals. These results indicate that non-bronchodilator doses of these phosphodiesterase inhibitors markedly reduce the allergen-induced development of bronchial hyperreactivity as well as airway inflammation, presumably by selectively inhibiting cellular migration. The results suggest that an orchestrated series of cellular interactions is involved in the development of bronchial hyperreactivity. It is concluded that phosphodiesterase inhibitors may be very useful in the treatment of bronchial asthma.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1995

Co-released adrenaline markedly facilitates noradrenaline overflow through prejunctional beta 2-adrenoceptors during swimming exercise.

The effect of intravenously applied (-)-adrenaline, taken up by and released from sympathetic nerves, on swimming exercise-induced noradrenaline overflow in permanently cannulated adrenal demedullated rats was studied. Adrenaline (100 ng/min) was infused for 2 h, during which a plasma concentration of 500 pg/ml (approximately 2.5 nM) was reached. One hour later plasma adrenaline had returned to undetectable levels. During swimming, adrenaline was released into the plasma in concentrations up to 133 pg/ml and the noradrenaline concentration was markedly enhanced as well. The total catecholamine increase amounted to 178% of control (saline infusion) in the first 3 min of swimming and 165% for the whole 20 min. Cocaine (2.5 mg/kg plus 0.05 mg/kg/min), infused together with adrenaline and continued throughout the experiment, prevented the exercise-induced release of adrenaline and no increase in plasma noradrenaline concentration was observed. Yohimbine (0.25 mg/kg) strongly further enhanced the exercise-induced overflow of both noradrenaline and adrenaline. This further increase was completely blocked by the selective beta 2-adrenoceptor antagonist ICI 118,551 ((+/-)-1-[(2,3-dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methyleth yl) amino]-2-butanol) (1.0 mg/kg). These results demonstrate that adrenaline can be taken up by sympathetic nerve endings through cocaine-sensitive uptake carriers and is released from these nerves during swimming exercise. Neuronally released adrenaline markedly enhances exercise-induced catecholamine overflow through activation of prejunctional beta 2-adrenoceptors.

Adrenergic beta-Antagonists↗
PubMed1995

Conditional involvement of muscarinic M1 receptors in vagally mediated contraction of guinea-pig bronchi.

The involvement of ganglionic muscarinic M1 receptors in vagally induced bronchoconstriction in guinea-pig airways is controversial. Therefore, we studied the effects of the M1-selective muscarinic receptor antagonist pirenzepine on vagus nerve (VNS, preganglionic) and electrical field stimulation (EFS, postganglionic)-induced contractions of the guinea-pig main bronchus under various experimental conditions. Using identical stimulation parameters for VNS and EFS (8V, 30 Hz, 0.5 ms, 5s every min), the amplitude of the VNS-induced twitch contractions was 30.4% of the EFS-induced responses, and pirenzepine showed 2.3-fold selectivity (pIC50-values 6.45 and 6.09, respectively) to inhibit vagally induced contractions. With the stimulation frequency for EFS lowered to match contraction levels obtained using VNS, pirenzepine was equipotent to inhibit both types of response at M3 receptor-selective concentrations, suggesting that M1 receptors are not involved. By contrast, when the stimulation episode was prolonged until plateau contraction (10-20 s), in the presence of the nicotinic antagonist hexamethonium (5 microM), the M2 receptor antagonist AQ-RA 741 (0.1 microM) and the beta-adrenoceptor antagonist timolol (1 microM), and again using matched VNS- and EFS-induced contraction levels, pirenzepine inhibited nerve stimulation-evoked responses in a biphasic manner, yielding pIC50-values of 8.12 (indicative of M1 receptor blockade) and 6.43 (indicative of M3 receptor blockade) for the first and second phase, respectively, while postganglionic stimulation showed a purely monophasic inhibition (pIC50 = 6.32). These results show that facilitatory muscarinic M1 receptors are involved in vagally mediated contraction of guinea-pig bronchi, under conditions of elevated neurotransmission and partial nicotinic receptor blockade.

Adrenergic beta-Antagonists↗
PubMed1995

Contribution of a cholinergic reflex mechanism to allergen-induced bronchial hyperreactivity in permanently instrumented, unrestrained guinea-pigs.

1. In conscious, permanently instrumented, unrestrained, ovalbumin-sensitized guinea-pigs the development of allergen-induced bronchial hyperreactivity to histamine- and methacholine-inhalation was investigated after the early as well as after the late asthmatic response. 2. The allergen-induced increase in bronchial reactivity to histamine was significantly higher than to methacholine. 3. The muscarinic receptor antagonist, ipratropium bromide (1.0 mM, 3 min inhalation), blocked methacholine-induced bronchoconstriction and caused a significant 1.7 fold inhibition of the histamine-induced bronchoconstriction of control animals. 4. A lower dose of ipratropium bromide (0.1 mM, 3 min inhalation) had no significant effect on histamine-induced bronchoconstriction in control animals, but significantly reduced the allergen-induced increase in bronchial reactivity to histamine between the early and late asthmatic response. At 1.0 mM ipratropium bromide, no further reduction was observed. 5. These results clearly indicate that an exaggerated cholinergic reflex mechanism contributes to allergen-induced bronchial hyperreactivity to histamine.

Allergens↗
PubMed1995

Dysfunction of muscarinic M2 receptors after the early allergic reaction: possible contribution to bronchial hyperresponsiveness in allergic guinea-pigs.

1. Using a guinea-pig model of allergic asthma, in which the animals display early (0-5 h) and late phase (8-23 h after antigen challenge) bronchoconstrictor reactions, the function of prejunctional inhibitory M2 and postjunctional M3 receptors in isolated tracheal preparations have been investigated. In addition, cardiac M2 receptor function in vitro and bronchial responsiveness to histamine in vivo were evaluated. 2. Sensitivity to inhaled histamine was increased 3.1 fold and 1.6 fold after the early and late allergic reactions (i.e. at 5 h and 23 h after a single ovalbumin challenge), respectively. At 23 h after the last of four allergen challenges, executed on four consecutive days, bronchial hyperresponsiveness to histamine was diminished to 1.3 fold. 3. After the early response, there was no change in cardiac muscarinic M2 receptor function, since in left atria pD2 (-log EC50) and Emax values of pilocarpine and pKB values of AQ-RA 741, a selective M2 receptor antagonist, were not significantly different from controls (unchallenged sensitized animals), and this also applied to methacholine pD2 values for muscarinic M3 receptors in tracheal smooth muscle. 4. Prejunctional inhibitory muscarinic M2 autoreceptors in airway smooth muscle were markedly dysfunctional after the early allergic response, since potentiation of electrically evoked twitch contractions of tracheal preparations by low concentrations of the M2-selective muscarinic receptor antagonists, gallamine, methoctramine, AQ-RA 741 and AF-DX 116, which is the result of M2 receptor blockade, was clearly and significantly diminished compared to controls. However, after the late response, both in single and repeatedly challenged animals, twitch potentiation was not significantly different from and similar to controls, indicating restoration of M2 receptor function during the late allergic reaction.5. It is concluded that dysfunction of muscarinic M2 autoreceptors in the airways of sensitized and challenged guinea-pigs is already present after the early allergic reaction, and that it has recovered after the late response. Since histamine-induced bronchoconstriction involves vagal pathways, the present results suggest that bronchial hyperresponsiveness to histamine is partly due to M2 auto receptor dysfunction, leading to increased release of acetylcholine.

Administration, Inhalation↗
PubMed1995

No evidence for a role of muscarinic M2 receptors in functional antagonism in bovine trachea.

1. The functional antagonism between methacholine- or histamine-induced contraction and beta-adrenoceptor-mediated relaxation was evaluated in bovine tracheal smooth muscle in vitro. In addition, the putative contribution of muscarinic M2 receptors mediating inhibition of beta-adrenoceptor-induced biochemical responses to this functional antagonism was investigated with the selective muscarinic antagonists, pirenzepine (M1 over M2), AF-DX 116 and gallamine (M2 over M3), and hexahydrosiladiphenidol (M3 over M2). 2. By use of isotonic tension measurement, contractions were induced with various concentrations of methacholine or histamine, and isoprenaline concentration-relaxation curves were obtained in the absence or presence of the muscarinic antagonists. Antagonist concentrations were chosen so as to produce selective blockade of M2 receptors (AF-DX 116 0.1 microM, gallamine 30 microM), or half-maximal blockade of M3 receptors (pirenzepine 0.1 microM, AF-DX 116 0.5 microM, hexahydrosiladiphenidol 0.03 microM). Since these latter antagonist concentrations mimicked KB values towards bovine tracheal smooth muscle M3 receptors, antagonist-induced decreases in contractile tone were compensated for by doubling the agonist concentration. 3. It was found that isoprenaline-induced relaxation of bovine tracheal smooth muscle preparations was dependent on the nature and the concentration of the contractile agonist used. Thus, isoprenaline pD2 (-log EC50) values were decreased 3.7 log units as a result of increasing cholinergic tone from 22 to 106%, and 2.4 log units by increasing histamine tone over a similar range. Furthermore, maximal relaxability of cholinergic tone decreased gradually from 100% at low to only 1.3% at supramaximal contraction levels, whereas with histamine almost complete relaxation was maintained at all concentrations applied. As a result, isoprenaline relaxation was clearly hampered with methacholine compared to histamine at equal levels of contractile tone.4. In the presence of gallamine, isoprenaline relaxation was facilitated for most concentrations of methacholine, and for all concentrations of histamine. These changes could be explained by the decreased contraction levels for both contractile agonists in the presence of gallamine.5. Isoprenaline-induced relaxation of cholinergic contraction was also facilitated by AF-DX 116 as well as by pirenzepine and hexahydrosiladiphenidol, and these (small) changes were again related to the(small) decreases in cholinergic contraction levels that were present in these experiments despite the additional administration of the agonist to readjust contractile tone. Similarly, changes in isoprenaline relaxation of histamine-induced tone could be explained by different contraction levels.6. These results can be explained by the sole involvement of muscarinic M3 receptors, and provide no evidence for a role of muscarinic M2 receptors in functional antagonism in bovine trachea. Furthermore,they stress the importance of taking into account non-cholinergic controls as well as contraction levels in these experiments.

Animals↗
PubMed1995

Noradrenaline-induced relaxation of rat oesophageal muscularis mucosae: mediation solely by innervated beta 3-adrenoceptors.

We investigated the effects of cocaine and corticosterone on the noradrenaline-induced relaxation of rat oesophageal smooth muscle in the absence and presence of the selective beta2-antagonist, ICI 111,551. It was found that the concentration-response curve (CRC) of noradrenaline was not shifted by ICI 118,551 at 1 microM, whereas a clear shift to the right was observed at 100 microM of the antagonist. In the presence of corticosterone (10 microM), CRC's were clearly shifted to the left; with cocaine (10 microM) additionally present, a further leftward shift was observed, indicating the involvement of both neuronal and extraneuronal uptake sites. It was concluded that the relaxation of rat oesophageal muscularis mucosae by noradrenaline is solely mediated by beta3-adrenoceptors which are sympathetically innervated.

Adrenergic beta-Antagonists↗
PubMed1995

Characterization of ORG 20241, a combined phosphodiesterase IV/III cyclic nucleotide phosphodiesterase inhibitor for asthma.

The pharmacological profile of a novel cyclic nucleotide phosphodiesterase (PDE) inhibitor, Org 20241, has been characterized. The compound selectively inhibits PDE IV (pIC50, 5.2-6.1) and PDE III (pIC50, 4.4-4.6) from animal and human tissues. Org 20241 relaxed preparations of bovine trachea (pD2, 5.9 and 5.4), guinea pig trachea (pD2, 6.2 and 4.9) and human bronchi (pD2, 5.3 and 4.7) for histamine and methacholine-induced contractions, respectively. Rolipram and Org 20241 inhibited leukotriene B4-induced thromboxaneB2 (IC50, 0.3 and 1.4 microM, respectively) and H2O2 (IC50, 2.1 and 0.4 microM, respectively) production in guinea pig eosinophils. In phenylephrine (0.3 microM) precontracted rabbit aorta preparations, the PDE III inhibitor Org 9935 (pD2, 6.3 and 6.1 in the presence and absence of endothelium, respectively) was the most effective relaxant, whereas Org 20241 (pD2, 5.3 and 5.4 in the presence and absence of endothelium, respectively) was more effective than rolipram (pD2, 4.6 and 4.1 in the presence and absence of endothelium, respectively). Org 20241 relaxed rabbit aorta preparations and airway preparations at similar concentrations. In electrically stimulated rabbit cardiac papillary muscles, Org 20241 had little effect on contractility at concentrations up to 30 microM. Lower concentrations (10 microM) potentiated the inotropic effect of Org 9935. Whereas the PDE III inhibitor milrinone (1-100 microM) enhanced the rate of repolarization of guinea pig papillary muscles and shortened the effective refractory period, Org 20241 and rolipram (1-100 microM) did not reduce the action potential duration. In the presence of Org 20241 or rolipram, isoproterenol did not produce a greater increase in the rate of repolarization or reduction in the effective refractory period than in the absence of these PDE inhibitors. Org 20241 is a dual PDE IV/III inhibitor with some PDE IV selectively. This compound relaxes airways smooth muscle and inhibits eosinophil activation. The data indicate that such PDE IV/III inhibitors may be effective for the long-term therapy of asthma.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed1994

Heterogeneity of prejunctional neuropeptide Y receptors inhibiting noradrenaline overflow in the portal vein of freely moving rats.

The effects of intraportal infusions of different doses of neuropeptide Y, its selective neuropeptide Y Y1 receptor analogue, [Leu31,Pro34]neuropeptide Y, and the Y2-selective C-terminal fragment, neuropeptide Y-(18-36), on basal and electrically evoked noradrenaline overflow in the portal vein as well as on mean arterial pressure and heart rate were investigated in permanently instrumented freely moving rats. Neuropeptide Y dose dependently (2-2000 ng/kg/min) attenuated the electrically evoked noradrenaline overflow and almost complete blockade was reached at the highest dose used. [Leu31,Pro34]Neuropeptide Y also dose dependently (20-20,000 ng/kg/min) attenuated the evoked overflow, reaching a maximum of 55% inhibition at the highest dose (20,000 ng/kg/min). Neuropeptide Y-(18-36) attenuated the evoked release only at 20,000 ng/kg/min (by 46%). Only at the highest dose did neuropeptide Y (2000 ng/kg/min) and [Leu31,Pro34]neuropeptide Y (20,000 ng/kg/min) significantly enhance mean arterial pressure and decrease heart rate and basal plasma noradrenaline levels, the latter two effects being due to the baroreceptor reflex. Neuropeptide Y-(18-36) did not influence these parameters at all doses used. The results indicate the presence of prejunctional neuropeptide Y Y1 receptors, and possibly the coexistence of Y1 and Y2 receptors, in the portal vein of freely moving rats, which in conjunction are able to inhibit markedly electrically evoked noradrenaline overflow. Postjunctional neuropeptide Y receptors mediating an increase in blood pressure in the freely moving rat are solely of the Y1 subtype.

Animals↗
PubMed1994

Dissociation between bronchial hyperreactivity in vivo and reduced beta-adrenoceptor sensitivity in vitro in allergen-challenged guinea pigs.

In a recently developed guinea pig model of allergic asthma, we investigated the relationships between allergen-induced bronchial hyperreactivity in vivo, tracheal smooth muscle function in vitro, and the number of inflammatory cells in the bronchoalveolar lavage. At 6 h after allergen provocation (after the early asthmatic reaction) bronchial hyperreactivity to histamine aerosol was observed, which was still present, but reduced, at 24 h after the challenge (after the late asthmatic reaction). The severity of bronchial hyperreactivity at 6 h and at 24 h after each of four daily allergen provocations was progressively reduced. The contractile properties of tracheal smooth muscle preparations in response to methacholine or histamine were not changed at 6 h and 24 h after a single allergen provocation, as well as at 24 h after the fourth of the repeated provocations. However, the sensitivity to isoprenaline-induced relaxation of a half-maximal contraction obtained with methacholine or histamine was significantly reduced at 24 h after either a single or the fourth of the repeated provocations. The time course of the reduced beta-adrenoceptor sensitivity in vitro did not correlate with that of bronchial hyperreactivity in vivo. However, it was parallelled by a progressive infiltration of inflammatory cells in the airways, suggesting that mediators from these cells may decrease airway smooth muscle beta-adrenoceptor sensitivity.

Allergens↗
PubMed1994

Role of histamine in allergen-induced asthmatic reactions, bronchial hyperreactivity and inflammation in unrestrained guinea pigs.

In a new model using conscious, unrestrained and ovalbumin-sensitized guinea pigs, we investigated the effects of the selective histamine H1 receptor antagonist, mepyramine, on the development of allergen-induced early and late asthmatic reactions, bronchial hyperreactivity and airway inflammation, having each animal as its own control. In guinea pigs responding to a first allergen exposure with an early as well as a late asthmatic reaction (82% of the animals) a second, identical, allergen provocation was performed, in the absence (control) or presence of 1 mg/ml mepyramine aerosol, inhaled for 10 min, 1 h before provocation. The mepyramine treatment significantly reduced both early and late asthmatic reactions and prevented the development of bronchial hyperreactivity to histamine and methacholine after both reactions. Examination of the bronchoalveolar lavage fluid 24 h after the second allergen provocation revealed a general reduction of inflammatory cells after mepyramine treatment. The results indicate that histamine, released during the early asthmatic reaction, contributes to the development of the late asthmatic reaction as well as of early and late bronchial hyperreactivity, possibly via an effect on airway inflammation.

Allergens↗
PubMed1994

Pre- and postganglionic stimulation-induced noradrenaline overflow is markedly facilitated by a prejunctional beta 2-adrenoceptor-mediated control mechanism in the pithed rat.

The aim of the study was to further explore the prejunctional beta-adrenoceptor-mediated control mechanism of noradrenaline release from sympathetic nerves in response to preganglionic nerve stimulation (PNS) and local nerve stimulation of the portal vein, respectively, in the pithed rat. Baseline values as well as the increments of mean arterial blood pressure (delta-BP), heart rate (delta-HR) and plasma noradrenaline levels (delta-NA) in response to four PNS episodes (0.8 Hz, 3 ms, 75 V for 45 s at 20 min intervals), respectively, were evaluated. Fenoterol administration (0.25 mg/kg, i.v.) reduced significantly the basal blood pressure but did not alter delta-BP in response to PNS. Basal heart rate markedly increased after fenoterol without any further change in heart rate induced by PNS. The beta 1-selective antagonist CGP 20712A attenuated delta-BP in response to PNS and prevented the fenoterol-induced increase in basal heart rate. The beta 2-selective antagonist ICI 118,551 per se did not change the blood pressure and heart rate values, but antagonized the fenoterol-induced decrease in basal blood pressure. Fenoterol enhanced plasma delta-NA in response to PNS by 105% in comparison to the corresponding control value. This effect of fenoterol could be blocked by pretreatment with ICI 118,551 but not with CGP 20712A (a selective beta 1-adrenoceptor antagonist) which per se did not significantly change plasma delta-NA. Repeated local stimulation of the portal vein (S1-S3, 2 Hz, 3 ms, 10 mA, for 120 s at 30 min intervals) increased portal plasma noradrenaline without changing mean blood pressure and heart rate in pithed rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗
PubMed1994

Relationships among allergen-induced early and late phase airway obstructions, bronchial hyperreactivity, and inflammation in conscious, unrestrained guinea pigs.

The relationship among allergen-induced early asthmatic reactions (EARs) and late asthmatic reactions (LARs), early (between EAR and LAR) and late (after LAR) changes in bronchial reactivity to histamine and infiltration of inflammatory cells into the airways were investigated with a new model of chronically instrumented, unrestrained, and ovalbumin-sensitized guinea pigs. Two different provocation strategies were examined. With the use of stepwise increasing allergen concentrations, all 21 animals responded with an EAR, which in 15 animals (71%) was followed by an LAR. By inhalation of a single allergen concentration for up to 15 minutes, 11 of 14 animals showed an EAR, which in 10 animals (71%) was followed by an LAR. One animal did not respond, whereas the remaining two showed only an LAR. At 6 hours (after the EAR) and 24 hours (after the LAR) after allergen provocation, a significant bronchial hyperreactivity (BHR) toward histamine aerosol was observed in the dual responding animals (both protocols), but not significant changes were observed in animals with a single EAR or a single LAR. Significant correlations were found between the initial increase in airway obstruction after allergen provocation and the severity of the EAR and LAR, as well as the early and late BHR; in addition, a significant correlation was found between the early and late BHR. In contrast, the severity of the LAR did not correlate with the BHR at 6 hours and 24 hours. At 6 hours, there was a marked tendency to an increase in the number of eosinophils and a significant increase in the number of neutrophils in the bronchoalveolar lavage. At 24 hours after provocation, the number of eosinophils and neutrophils was significantly enhanced. These data suggest that early activation of mast cells and/or inflammatory leukocytes may determine the development of the LAR, as well as the early and late BHR, although there appears to be no causal relationship between the BHR at both time points and the severity of the LAR. The relationships among allergen-induced EAR and LAR, early and late BHR, and airway inflammation observed in this new guinea pig model are strikingly similar to those observed in patients with asthma.

Airway Obstruction↗
PubMed1994

The importance of eosinophil activation for the development of allergen-induced bronchial hyperreactivity in conscious, unrestrained guinea-pigs.

Using a newly developed guinea-pig model of asthma, characterized by allergen-induced early and late phase asthmatic reactions, bronchial hyperreactivity (BHR) and airway inflammation, the importance of eosinophil activation for the development of BHR to inhaled histamine was investigated at 6 h (after the early reaction) and 24 h (after the late reaction) after allergen provocation. Eosinophil activation was assessed by a sensitive kinetic assay for eosinophil peroxidase (EPO) activity, suitable for bronchoalveolar lavage (BAL) analysis. A significant 2.9-fold (P < 0.01) increase in bronchial reactivity to histamine was observed at 6 h after allergen exposure, which was associated with a 2.9-fold increase in the number of eosinophils (P < 0.05) and a 6.7-fold increase in EPO activity (P < 0.01) in the BAL fluid. At 24 h after allergen exposure the bronchial reactivity to histamine was lower (1.7-fold), but still significantly enhanced (P < 0.01). By contrast, the number of eosinophils was further increased compared with 6 h after provocation (3.8-fold, P < 0.05), while the EPO activity remained stable at 6 h levels. The number of eosinophils was significantly correlated with EPO activity at 6 h (r = 0.62; P < 0.05), but not at 24 h after provocation. No significant correlation was observed between the number of eosinophils in the BAL fluid and BHR to histamine at either time point.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Influence of the baroreceptor reflex on the modulation of noradrenaline overflow through prejunctional receptors in the portal vein of freely moving rats.

1. The effects of alterations in mean arterial blood pressure (MAP), as induced by vasoactive drugs, on heart rate (HR), basal noradrenaline concentration and electrically evoked noradrenaline overflow and on blood flow in the portal vein of freely moving rats, were investigated. 2. By infusion of sodium nitroprusside or phenylephrine (0.5, 1.0 and 2.5 micrograms kg-1 min-1), MAP was altered over a range of 50 to 150 mmHg. The resulting changes in HR showed a sigmoidal relationship with MAP. Noradrenaline overflow increased linearly when MAP was decreased; when MAP was increased, however, noradrenaline levels only decreased to 70% and reached a plateau from 125 mmHg onwards. 3. Nitroprusside (2.5 micrograms kg-1 min-1) and fenoterol (0.25 mg kg-1) decreased MAP to the same extent (-46 mmHg). HR and basal noradrenaline concentration, however, were increased to a higher extent by fenoterol (+192 beats min-1; +373 pg ml-1, respectively) than by nitroprusside (+78 beats min-1; +206 pg ml-1, respectively). Electrically evoked overflow was not changed at all after nitroprusside, whereas fenoterol induced an increase to 206% of control. 4. Phenylephrine (2.5 micrograms kg-1 min-1) and angiotensin II (1 microgram kg-1 min-1) increased MAP to the same extent (to 155 and 161 mmHg, respectively). Basal noradrenaline concentration decreased by 30% after phenylephrine, whereas angiotensin II increased noradrenaline levels to 226% of control. Evoked noradrenaline overflow was not changed after phenylephrine but was increased to 204% of control after angiotensin II.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
PubMed1994

Sustained prejunctional facilitation of noradrenergic neurotransmission by adrenaline as a co-transmitter in the portal vein of freely moving rats.

1. The duration of the facilitatory effect of adrenaline on the electrically evoked overflow of noradrenaline was studied in the portal vein of permanently adreno-demedullated freely moving rats. 2. Rats were infused with adrenaline (20 or 100 ng min-1) for 2 h. After an interval of 1 h, when plasma adrenaline had returned to undetectable levels, electrical stimulation resulted in an enhanced catecholamine overflow amounting to 219% (noradrenaline) and 241% (noradrenaline plus adrenaline) of control (saline infusion), respectively. 3. When stimulation was applied again, in the same animal, at 24, 48 and 72 h after the first stimulation episode, the evoked noradrenaline overflow was 150, 111 and 102% (after 20 ng ml-1 adrenaline) and 158, 134 and 105% (after 100 ng min-1 adrenaline) of control. 4. The beta 2-adrenoceptor antagonist, ICI 118,551 (0.3 mg kg-1), blocked the facilitatory effect obtained after the 100 ng min-1 adrenaline infusion on all days. 5. The results show that adrenaline, after being taken up by and released from sympathetic nerve terminals, is able to facilitate the evoked noradrenaline overflow through activation of prejunctional beta 2-adrenoceptors for at least 48 h after administration.

Adrenal Medulla↗